Genetics in Lupus

In this article, "lupus" will mean systemic
lupus erythematosus. The most common symptoms of lupus are fever,
rash, and arthritis. Women tend to develop lupus more commonly than
men, and people of African descent develop lupus more commonly than
people of European descent.

Lupus is only one of many "auto-immune"
diseases. "Auto" means that the body has an immune reaction against
itself. Rheumatoid arthritis and scleroderma are also auto-immune
diseases.

Given that lupus, rheumatoid arthritis,
and scleroderma are all auto-immune disorders, how do physicians
tell them apart? The answer is surprisingly old-fashioned. In the
case of lupus, physicians compare the patient's symptoms and blood
tests to a list of 11 criteria that experts agreed on in 1982. If
the patient's data match 4 or more of the criteria, a diagnosis
of lupus can be made.

Auto-immunity causes some, but
not all, symptoms of lupus. Other symptoms are caused by problems
cleaning up the remnants of auto-immune attacks. These remnants
are called "immune complexes" and they circulate in the blood,
where they can irritate the inside wall of blood vessels.

Thus, lupus is more correctly viewed
as arising from problems with control of the immune system.
It happens that these control problems show up as auto-immunity.

Can lupus run in families?

Yes. This was first observed in the 1950s.
More recent studies show that the brother or sister of a lupus patient
is 25 times more likely to develop lupus than someone in the general
population.

When lupus runs in families,
is the reason genes or environment?

As in most human disease, the answer appears
to be "both." Lupus has strong genetic components. It has environmental
components as well.

Lupus in twins

Studies
of twins provide the clearest insight into the relative importance
of genes and environment. For example, in 1992 researchers
looked at 107 pairs of twins in which at least one twin had
lupus.

Type of twin pair

Number of twin pairs

Twin pairs in which both twins had lupus("concordance rate")

Identical twins

45

24%
(11 of 45 pairs)

Non-identical twins

62

2%
(1 of 62 pairs)

If lupus were governed only by genes, then every time one
identical twin has lupus, the other should have it, too. (Because
identical twins have the same genes.) In other words, the
"concordance rate" should be 100%. The table shows, however,
that there is a 24% concordance between identical twins. This
shows that lupus has an environmental component.

If lupus were purely an environmental
condition, then genes should make no difference at all. The
concordance rate would be the same for identical twins and
non-identical twins. The table shows, however, that the concordance
rate is more than ten times higher in identical twins (24%)
as compared with non-identical twins (2%). This shows that
lupus has a genetic component.

What genes are involved
in lupus?

In 95% of cases, genetic susceptibility
to lupus is not caused by a single gene. Multiple genes are involved.
Identifying them has been slow because different genes seem to be
at work in different ethnic groups.

HLA Genes

Because lupus is an auto-immune disease,
scientists first studied genes that control the immune system. The
HLA family of genes, all located on the short arm of chromosome
6 , are important controllers of the immune system. They are divided
into 3 classes:

HLA class I genes -- These genes have
little to do with lupus.

HLA class II genes -- Many genes in this
group are linked to lupus:

The combination of the DR3 and DQ2
variants, or the DR2 and DQ6 variants raise the risk of lupus
by a factor of 2 or 3. These genes account for only a small
part of the genetic risk for lupus.

Many studies of class II genes show
no links with lupus. Scientists, therefore, tried dividing
lupus into subtypes, according to the results of various blood
tests. When they did this, many links between class II genes
and lupus subtypes were seen. This suggests that systemic
lupus erythematosus is not one disease, but several similar
diseases.

HLA class III genes -- Many genes in
this group are linked to lupus:

The C4A and C2 genes are discussed
below, in the section on "complement genes."

Certain variants of the TNF genes
raise the risk of lupus in some ethnic groups.

Complement Genes

Less than 5% of patients with lupus owe
their genetic susceptibility to a single gene. Many of these genes
relate to the body's "complement system." The complement system
is part of the immune system.

The C1q genes on chromosome 1 sometimes
code for a variant of the C1q complement protein that is less
efficient than usual. When this happens, lupus can result, especially
in children. The C1q protein has both an "attack" function and
a "clean-up" function in the immune system. Scientists believe
that lupus can be triggered if the remnants of an immune system
attack are not cleaned up efficiently.

Deficiencies of other complement proteins
also lead to lupus, including deficiencies of the proteins coded
by the C4A and C2 genes on chromosome 6 , and the C1r and C1s
genes on chromosome 12.

The MBL2 gene on chromosome 10 is the
blueprint for a protein called mannose binding protein that is
similar in shape to C1q. In Spanish and African-American populations,
certain variants of this gene are more common in persons with
lupus. Combinations of this gene and the C4 gene are more strongly
associated with lupus than either gene alone.

Other Genes

Three studies have scanned the entire
human genome for linkages with lupus. One part of the short arm
of chromosome 1 was positive in all 3 studies. Other parts were
positive in two of three studies. These results were reassuring,
because other studies had identified suspicious genes in precisely
these areas of chromosome 1:

The FCGR2A gene influences how the
body cleans up the results of immune attacks. Certain variants
of this gene raise the risk of kidney disease in African-Americans
with lupus.

The APT1LG1 and ADPRT genes are part
of the body's system that controls the lifespan of cells ("apoptosis").
Similar genes in laboratory mice are linked to lupus, but
more studies of humans are needed.

Regions on chromosomes 2, 6, 14, 16,
and 20 also came up positive in at least two of the whole-genome
studies mentioned above.

Another powerful genetic effect is gender.
Ninety percent of all lupus cases are in women.

Actually, the C1q protein is not a
single protein coded by a single gene. Nature is often more
complicated than it first appears.

Strictly
speaking, C1q is the name for a complex of 3 different types
of proteins, called A, B, and C. Each of these 3 proteins
is made from its own gene on chromosome 1 . Six copies of
A, B, and C group together, meaning that C1q is actually a
complex of 18 individual proteins! Scientists are not sure
whether the A, B, or C gene causes the problem that leads
to lupus.

Two heart medications, procainamide
and hydralazine, can trigger an illness that is similar to
systemic lupus erythematosus, but not identical. This illness
is called drug-induced lupus. At least two genes can contribute
to susceptibility to drug-induced lupus:

The N-acetyl-transferase 2 gene
on chromosome 8 influences how the body processes toxins.
It plays a role in several human diseases. There are 2 major
variants of the gene: "fast" and "slow." People with the
"slow" variant are more likely to develop drug-induced lupus.

The HLA class II genes on chromosome
6 , are also involved: People with the DR4 variant are more
likely to develop drug-induced lupus.

Drug-induced lupus usually goes away
when the offending medication is stopped, although it sometimes
takes years to resolve completely.

What environmental
factors are involved in lupus?

It has been difficult to pin down the environmental
components of lupus. The following factors are the best known:

Medications -- As described above, the
cardiac medications procainamide and hydralazine can trigger an
illness similar to lupus. Of course, most people who take these
medications do not develop an illness. We do not know why.

Ultraviolet radiation -- Sunlight can
worsen the skin problems of people with lupus.

Sex hormones -- Women get lupus more
commonly than men. And certain men who have higher-than-normal
levels of female sex hormones (due to a medical condition called
Klinefelter syndrome) develop lupus at a rate between that of
women and other men.

The evidence for other environmental factors
-- including infections, diet, and chemical agents and toxins --
is weak and inconsistent. Once the genetics of lupus is better clarified,
it will be easier to determine the environmental factors influencing
the disease.

When lupus runs
in families, why don't all family members have it?

It helps to frame this question a little
differently.... All members of a family do not have the same height,
weight, and face. So, it makes sense that they don't all have the
same conditions and diseases -- or the same susceptibility to various
diseases.

Here again, it's genetic and environmental
differences that explain differences in our appearance and health.
Some family members will inherit genes that predispose to lupus,
and others will not. Some family members will be exposed to environmental
agents that trigger disease, and others will not.

There is no lupus in
my family. Does this mean it will never occur in my family?

No. Anyone can develop lupus. About 90%
of people with lupus do not have an immediate family member with
lupus. But if someone in your family does have lupus, you are at
greater risk.

How will discoveries
about DNA help people and families with lupus?

Further discoveries about lupus genes will
lead to more individualized medicine. Prevention, diagnosis, treatment,
and prognosis will be personalized, based largely on the strengths
and weaknesses found in a person's genes.

Treatment -- better use of existing treatments

Several medicines have been approved to
treat lupus. How does your physician know which is best for you?
Part of the answer may be in your genes.

In this article, we've seen how specific
genes influence the development and progression of a complex condition
-- lupus. Similarly, specific genes may influence the responses
to different treatments. Better genetic information could explain
why some drugs work better in some people than others. This will
make choosing treatments less hit-and-miss than in the past.

Treatment -- discovery of new treatments

Whenever scientists discover a gene involved
in lupus, it's a doorway to designing new treatments. If the gene
is over-active, then scientists can look for ways to turn it off
or interfere with its activity. If the gene is under-active or
broken, then scientists can look for ways to turn it on or increase
its activity.

Prevention, Diagnosis, Prognosis

Prevention, diagnosis, and
prognosis
all improve when our ability to calculate risk improves. Scientists
believe genes will tell us a lot about the risk of developing
lupus and the progression of lupus.